Objective: This systematic review and meta-analyses aim to synthesize longitudinal evidence of GBA variants as a prognostic factor for all-cause mortality in Parkinson’s disease (PD).

Background:

Variants in the glucosylceramidase beta (GBA) gene are the most common genetic risk factor for Parkinson’s disease (PD). While GBA-PD is associated with more rapid motor and cognitive decline, evidence regarding its impact on survival remains debatable.

Method: We searched MEDLINE, Embase, Cochrane (CENTRAL), ClinicalTrials.gov, and WHO International Clinical Trials Registry Platform (ICTRP) for studies comparing mortality in GBA-PD versus non-carriers from inception to September 2025. Risk of bias was assessed using the Quality in Prognosis Studies (QUIPS) tool. Hazard Ratios (HR) were pooled using a random-effects meta-analysis. Subgroup analyses were performed based on variant severity.

Results: Eight studies (N = 13,690) were included. The primary meta-analysis (n = 4,947) revealed that GBA variants were associated with a significantly increased risk of all-cause mortality compared to non-carriers (HR 1.53, 95% CI 1.24–1.87; I² = 0.7%). Subgroup analysis indicated a potential dose-dependent effect, with severe mutations conferring higher risk (HR 1.87; 95% CI 1.24–2.82) than mild variants (HR 1.38; 95% CI 1.03–1.83).

Conclusion: GBA variants are a significant prognostic marker for reduced survival in PD. This risk appears driven by variant pathogenicity and is often, though not exclusively, mediated by dementia. Limitations include the heterogeneity of screening methods and predominance of European ancestry in study populations. Ultimately, GBA status should be considered a significant prognostic factor for patient stratification in clinical trials and management. Future research is required in relation to targeted treatment in this population and may lead to disease-modification.

Chan N, Raphael A, Kim J, Haryanto A, Heshmat S, Khoo TK. GBA1 variants and mortality in Parkinson’s disease: A systematic review and meta-analysis. Journal of Parkinson’s Disease. 2026;0(0). doi:10.1177/1877718X261470604. © 2026 The authors, licensed under CC BY-NC 4.0: https://creativecommons.org/licenses/by-nc/4.0/.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/prognostic-impact-of-gba-variants-on-mortality-in-parkinsons-disease-a-systematic-review-and-meta-analysis/